LIGHT, (lymphotoxin-like, exhibits inducible expression and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes) is one potential cytokine target that has been implicated in the processes of chronic inflammatory autoimmune diseases (Immunity. 1998 January; 8(1):21-30, “LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator”, Mauri D N et al). As a member of the TNF superfamily (TNFSF) of ligands, LIGHT is also known as TNFSF14 or CD258. LIGHT is expressed on the surface of T cells upon activation in a tightly regulated manner appearing within 4 hours, peaking by 12-24 hours and disappearing by 48 hours (J Biol Chem. 2002 Nov. 8; 277(45):42841-51. Epub 2002 Sep. 4, “Mechanisms regulating expression of the tumor necrosis factor-related LIGHT gene. Role of calcium-signaling pathway in the transcriptional control”, Castellano R et al). However, LIGHT is also present at detectable levels constitutively on the surface of immature dendritic cells (J Immunol. 2000 Apr. 15; 164(8):4105-10, “LIGHT, a TNF-like molecule, costimulates T cell proliferation and is required for dendritic cell-mediated allogeneic T cell response”, Tamada K et al) and on T cells and natural killer (NK) cells of the gut (J Immunol. 2005 Jan. 15; 174(2):646-53, “LIGHT is constitutively expressed on T and NK cells in the human gut and can be induced by CD2-mediated signalling”, Cohavy O et al). LIGHT mediates its biologic effects by binding three TNF superfamily receptors including the lymphotoxin β receptor (LTβR) (Science. 1994 Apr. 29; 264(5159):707-10, “A lymphotoxin-beta-specific receptor”, Crowe P D et al; J Immunol. 1997 Oct. 1; 159(7):3288-98, “Characterization of lymphotoxin-alpha beta complexes on the surface of mouse lymphocytes”, Browning J L et al), the herpes virus entry mediator (HVEM) (Cell. 1996 Nov. 1; 87(3):427-36, “Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family”, Montgomery R I et al), and decoy receptor 3 (DcR3) (J Biol Chem. 1999 May 14; 274(20):13733-6, “A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis”, Yu K Y et al).
Mice treated with an inhibitory LTβR-Fc fusion protein reduced the inflammatory symptoms in the CD4+CD45RBhigh T cell transfer model of colitis, a CD4+ T cell-mediated pathology (Gastroenterology. 1998 December; 115(6):1464-75, “Both the lymphotoxin and tumor necrosis factor pathways are involved in experimental murine models of colitis”, Mackay F et al). Constitutive transgenic T cell specific expression of LIGHT also has been shown to lead to severe intestinal inflammation with autoimmune-like pathology resembling human inflammatory bowel disease (IBD) (J Immunol. 2005 Jun. 15; 174(12):8173-82, “The critical role of LIGHT in promoting intestinal inflammation and Crohn's disease”, Wang J et al; J Immunol. 2001 Dec. 1; 167(11):6330-7, “Constitutive expression of LIGHT on T cells leads to lymphocyte activation, inflammation, and tissue destruction”, Shaikh R B et al; J Immunol. 2001 Nov. 1; 167(9):5099-105, “The critical role of LIGHT, a TNF family member, in T cell development”, Wang J et al; J Clin Invest. 2004 March; 113(6):826-35, “Dysregulated LIGHT expression on T cells mediates intestinal inflammation and contributes to IgA nephropathy”, Wang J et al). LIGHT-expressing lymphocytes can induce IBD-like symptoms (e.g., cytokine profiles of human Crohn's disease, fissuring ulcers, ileitis, and increases in colonic IFN-γ and TNF) when mesenteric lymph node cells from LIGHT transgenic animals are transferred to RAG−/− (J Immunol. 2005 Jun. 15; 174(12):8173-82, “The critical role of LIGHT in promoting intestinal inflammation and Crohn's disease”, Wang J et al). In human disease, increases of LIGHT expression were observed in patients with active Crohn's disease (Cohavy et al 2005 supra; Wang et al 2005 supra; Wang et al 2004 supra; J Immunol. 2004 Jul. 1; 173(1):251-8, “LIGHT expression by mucosal T cells may regulate IFN-gamma expression in the intestine”, Cohavy O et al). LIGHT has also been demonstrated to be elevated in gut T cells of IBD patients (Cohavy et al 2004 supra). Genetic evidence also supports a role for LIGHT in IBD (J Immunol. 2001 Nov. 1; 167(9):5122-8, “Genomic characterization of LIGHT reveals linkage to an immune response locus on chromosome 19p13.3 and distinct isoforms generated by alternate splicing or proteolysis”, Granger S W et al; Am J Hum Genet. 2000 June; 66(6):1863-70. Epub 2000 Apr. 21, “Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci”, Rioux J D et al; Inflamm Bowel Dis. 2004 May; 10(3):173-81, “Inflammatory bowel disease is linked to 19p13 and associated with ICAM-12, Low J H et al; Gastroenterology. 2003 February; 124(2):521-36, “The genetics of inflammatory bowel disease”, Bonen D K, Cho J H).
Human LIGHT (hLIGHT) has also been implicated in graft-versus-host disease (GvHD). For example, LIGHT has been shown to provide potent costimulatory activity for T cells, enhancing proliferation and the production of Th1 cytokines independent of the B7-CD28 pathway (see, e.g., Tamada et al 2000 supra). Blocking of LIGHT-HVEM costimulation by either anti-HVEM monoclonal antibodies, HVEM-Ig, or LTβR fusion protein inhibits allogeneic T cell responses (see, e.g., Tamada et al 2000 supra; J Immunol. 1998 Aug. 15; 161(4):1786-94, “Antibodies to TR2 (herpesvirus entry mediator), a new member of the TNF receptor superfamily, block T cell proliferation, expression of activation markers, and production of cytokines”, Harrop J A et al). Furthermore, in vivo administration of LTβR-Ig or murine anti-LIGHT antibodies inhibits anti-host cytotoxic T lymphocyte (CTL) responses in a murine acute GvHD model (Nat Med. 2000 March; 6(3):283-9, “Modulation of T-cell-mediated immunity in tumor and graft-versus-host disease models through the LIGHT co-stimulatory pathway”, Tamada K et al).
Inflammatory bowel diseases (IBDs)—mostly represented by Crohn's disease (CD) and ulcerative colitis (UC)—are a group of inflammatory disorders of the gastrointestinal tract characterized by an abnormal immune response to antigens of the intestinal content that leads to a persistent inflammatory state. Reference is made to World J Gastroenterol. 2010 Sep. 14; 16(34):4264-71, “Intestinal epithelial cells in inflammatory bowel diseases”, Roda G et al. The pathogenesis of inflammatory bowel diseases (IBDs) seems to involve a primary defect in one or more of the elements responsible for the maintenance of intestinal homeostasis and oral tolerance. The most important element is represented by the intestinal barrier, a complex system formed mostly by intestinal epithelial cells (IECs). IECs have an active role in producing mucus and regulating its composition; they provide a physical barrier capable of controlling antigen traffic through the intestinal mucosa. At the same time, they are able to play the role of non-professional antigen presenting cells, by processing and presenting antigens directly to the cells of the intestinal immune system. On the other hand, immune cells regulate epithelial growth and differentiation, producing a continuous bi-directional cross-talk within the barrier. Several alterations of the barrier function have been identified in IBD, starting from mucus features up to its components, from epithelial junctions up to the Toll-like receptors, and altered immune responses. It remains to be understood whether these defects are primary causes of epithelial damage or secondary effects. The authors review the possible role of the epithelial barrier and particularly describe the role of IECs in the pathogenesis of IBD.